Thyroid T3 secretion compensates for peripheral T4-T3 conversion

In health, what happens when your tissues don’t convert enough T4 into T3 hormone? Your healthy thyroid secretes more T3.

The healthy thyroid gland’s synthesis of T3 de novo (from raw materials of iodine and tyrosine) under the stimulation of a healthy TSH can maintain your circulating T3 supply. This prevent tissues from becoming hypothyroid when they can’t convert enough T4 into T3 locally.

This principle has been demonstrated in human models in Pilo’s study in 1990, and several other scientific studies. It is

“the capacity of the hypothalamic-pituitary-thyroid axis to compensate for the lack of peripheral T4-to-T3 conversion.”

(Marsili et al, 2011)

The healthy TSH-stimulated thyroid has the flexibility to secrete more T3, when needed, to compensate for poor peripheral T4-T3 conversion (in tissues beyond the thyroid).

Scientists who observed the mouse’s thyroid gland secretion adapt to life without D1 and D2 enzymes, who could not convert T4 to T3, emphasized this lesson:

“the importance of the thyroid per se as a source of T₃.”

(Galton et al, 2009)

However, a common generalization expressed over and over in scientific articles dismisses the thyroid’s importance as a source of T3 in humans.

We are given the impression that peripheral T4-T3 conversion don’t vary much across individuals, and a human thyroid is not capable of adaptive compensation in its T3 secretion rate, because a reduction in conversion rate is unthinkable. The ratio for humans is expressed as if it is fixed in stone:

“20% of daily T3 comes from the thyroid,
80% from peripheral conversion of T4.”

This idea of an inflexible ratio is an inaccurate representation of statistical averages from a famous scientific research article from 1990. It’s a narrow-minded concept that requires correction from the article itself and from confirming studies.

This idea of limited thyroidal T3 secretion, of a fixed, inflexible thyroidal T3 secretion, is found all over thyroid therapy literature, such as in this passage in the American Thyroid Association (ATA) 2014 guidelines by Jonklaas et al:

“Approximately 85 mcg of T4 is secreted by the thyroid gland daily. Of the total daily T3 production of about 33 mcg in normal man, approximately 80% (about 26 mcg) arises from peripheral conversion from T4, and only about 20% (approximately 6.5 mcg) derives from direct thyroidal secretion (34).”

This passage begins by emphasizing T4 and its approximate contribution to daily T3 production rate, and ends by diminishing “only about 20%” from “thyroidal secretion.”

What is item “(34)” cited at the end of the passage? It is Alessandro Pilo and team’s famous 1990 kinetic study of T4 and T3 hormone economy in healthy humans (or as the ATA say, “normal man”).

Most people reading this passage will believe the ATA is providing accurate figures (85 mcg, 33 mcg, 26 mcg, and 6.5 mcg). No. They didn’t count on having a humble thyroid patient fact-checking their calculations.

Pilo’s study, which they cite, did NOT discover, as the ATA states, that “85 mcg of T4 is secreted by the thyroid gland daily.” Nor did it find that 20% was a good estimate of the rate of T3 secretion from all human thyroids. The ATA’s word “approximately” is no excuse. They give extremely precise numbers, and yet they are off by 15 micrograms of T4 based on Pilo’s article.

Why does it matter that they are off by 15 micrograms here or there?

Because such narrow calculations have become fundamental premises on which people have built many narrow, lopsided theories to defend their preferred therapy practices.

Thyroid therapy has become a game of numbers. When medicine tries to replace a flexible gland with a static dose of hormone, people’s health and well being are based on precise microgram doses, lab reference ranges, and theoretical concepts like ratios.

Our systems have to respect the wide ranges of individual variation that nature reveals and science has documented. If they misrepresent the wide variations in secretion and conversion rates as if they are narrow averages that apply to everyone, it can have devastating implications for individuals who aren’t statistically average.

How would you like to live with a suboptimal FT3 level for the rest of your life because your gullible doctor reveres the ATA and believes you are a “normal man” or woman who can live happily on a ratio of 85 mcg / day of LT4 to 6.5 mcg of LT3 as long as it normalizes your TSH?

What if, under the cover of the statistically normal TSH, this dosing strategy is not providing the T3/T4 ratio your thyroid gland would have provided in health?

The details from Pilo’s 1990 study are more accommodating of individual diversity than the ATA wants them to be.

In this old study of 14 healthy human beings, they estimated one person had 42% of their total T3 supply from their thyroid gland and 58% came from peripheral T4-T3 conversion.

• That’s not a 20/80 T3 secretion / conversion ratio. That’s more than 2x the 20% people are told.

In another patient in the same study, 6.5% came from their thyroid gland and 93.5% from peripheral conversion.

• That’s not a 20/80 ratio, either. That’s less than 1/2 the 20%.

Yet the idea of 20% of T3 supply from the thyroid is cited today over and over as if it is as universal as the law of gravity.

Sadly, squeezing a such a wide range of human variation into a static ratio is harmful when applied to millions of diverse individuals on thyroid therapy. It has caused great injury to those whose peripheral thyroid hormone metabolism produces a significant T3 deficit, people like the man whose thyroid had to step up its game and secrete 42% of his T3 supply. Not every woman or man fits the average “normal man” parameters.

Pilo’s study is by no means perfect, but its published data set is worthy of a detailed look in the new color-coded tables I provide in today’s post.

Summary / Abstract

Pilo’s aims and methods

First, here’s the basics of Pilo’s study.

It had nothing to do with deciding what dosage ratios of T4 and T3 hormone were appropriate for thyroid-disabled or thyroidless people. But that’s how it is often misused today, ever since Escobar-Morreale and team proposed clinical trials of thyroid hormone combination therapy based on Pilo’s averages.

Pilo’s team of researchers were trying to understand how much T4 and T3 were secreted and how much T4 became T3 outside the thyroid gland in healthy people with healthy thyroids who had a TSH between 1 and 2 mU/L.

To learn this, the researchers performed an intensive biochemical experiment involving radioactive-iodine-tagged T4 and T3 molecules ([125-I]T4 and [131-I]T3) injected into healthy patients. They attempted to distinguish the conversion of tagged hormones from the non-tagged hormones secreted by the thyroid gland to find out how much came from the thyroid gland.

Combining complicated mathematics, Sephadex gel filtration chromatography, and radioimunoassay testing methods, they measured hormone concentrations.

Based on these measurements, they used theoretical models to estimate each human subject’s global daily T4-T3 conversion rate (CR) and thyroidal secretion rate (SR) of T4 and T3 as fractions of the total amounts of circulating T3 and T4 in bloodstream.

Key flaws in the study

Contemporary thyroid science’s overreliance on this flawed and outdated study, which has never been replicated, is frankly puzzling.

A lot of these scientist’s work was based on refining older theoretical models of thyroid hormone exchange across “compartments” in the human body. Their models were rough. They embedded at least five major inaccuracies and blind spots:

1. Their study pre-dated our modern understanding of transmembrane thyroid hormone transporters and the three thyroid hormone deiodinases. These are two major pillars of the thyroid hormone economy. As a result, every time we cite 20/80, we are returning to this incomplete, outdated metabolic model.

2. There is no sign of any investigation into the subjects’ conversion of T4 into “Reverse T3” (RT3), which would have made their calculations more precise. By verifying the concentrations of the 3rd most abundant thyroid hormone, the most significant “byproduct” of T4 metabolism, their theory-based mathematical estimates of peripheral T3 would have been confirmed.

Measuring both RT3 and T3 is like measuring how much heat and light is produced from a light bulb when measuring its energy efficiency.

Without this simple check and balance, one wonders whether their mass chromatography techniques could have distinguished T3 from RT3 molecules, given that these two hormones have the same molar mass of 650.97 (according to PubChem).

3. They also did not fully take into account the intrathyroidal conversion of T4 into T3 as blood flows through the thyroid (See Berberich et al, 2018), strangely assuming that thyroid “secretion” was synonymous only with “synthesis,” and that “conversion” was only peripheral outside the thyroid gland.

4. They didn’t account for the way TSH hormone can powerfully shift ratios of T3 and T4 synthesis (Citterio et al) and T4-T3 conversion. They didn’t study humans at various TSH levels to observe this conversion-boosting factor in action. They only studied people with TSH in the narrow range from 1-2 pmol/L. They also used a TSH assay that only gave one digit after the decimal point: likely an old, 2nd generation assay.

5. Their subjects were iodine-overdosed every day during the study. This was a common practice in such kinetic studies of the era because it flooded the body with non-radioactive iodine and lowered the percent of injected radioactive iodine that could be recirculated through the thyroid gland as T4 and T3 during the 8-day experiment.

However, acute iodine overdosing also biases T4 and T3 secretion rate from the thyroid–the rate their experiment was trying to discover.  

Despite these flaws and others revealed below, the details and insights found within Pilo’s study are still valuable.

One should not throw away gems of truth just because they are rough-hewn. Older studies in thyroid science still have a lot to say.

Findings

Older studies like Pilo’s often provided detailed data tables in their articles, with patient-by-patient data, not just averages and ranges. This detail enables intelligent analysis of human variation. This is invaluable to clinicians who treat individuals, not averages.

Pilo’s article contains many complex tables, like Table 2 shown below. (No, dear reader, you don’t have to read the fine print! I’m just giving you an idea of how much data is in Table 3 alone.)

Data tables like this one form the basis of my reformatted tables below.

From this table, I’ve obtained the Secretion Rates of T4 and T3 (SR-T4, SR-T3) on the right two columns, and the daily Production Rate of T3 (PR-T3) per day, per square meter of body surface. Other data used below come from their additional tables.

Thyroidal T4:T3 Secretion Rates and Ratios

One of the major misrepresentations of Pilo’s article comes from relying on the average thyroidal secretion rates and ratios.

The mere averages do not begin to represent the wide range of diverse data.

In an earlier post, I provided a scatterplot to show how ridiculous it is to imagine that “the” thyroid gland secretes approximately 14 micrograms of T4 for every microgram of T3, an average ratio derived from this study.

Each person’s T4-T3 secretion ratio is a blue dot.

Where is the pattern?

Do you see a central tendency or cluster of dots?

Does the dotted trendline help you see a trend in this constellation?

Case seven (C7) represents a ratio closest to the statistical average ratio of 1 mcg T3 to 14.5 mcg T4. Could you have guessed that dot was the average?

This is a situation in statistics when an average is not meaningful.

Table view

The dots in the scatterplot graph above correlate with the data in the right-hand column in the table below.

As you can see, patient 3 (in row 3 of the table body) has a thyroidal secretion ratio of 6.4 micrograms of T4 per microgram of T3.

Sorting a heat-mapped table by a single column helps one see patterns, if they exist.

This table’s data is sorted by the middle column in green that has the smooth gradation of white at the top to dark green at the bottom: the T4 secretion rate.

The yellow-colored cells in the averages are derived from Pilo’s Table 3 above. The blue averages are calculated from his data using simple math.

As you can see in the graph below, once I multiplied Pilo’s data on the daily thyroidal secretion rate of T4 by the surface area of the 14 patients’ bodies in square meters (given elsewhere by Pilo), I obtained the second green column of data showing these patients’ T4 secretion amount per day.

The average T4 secretion in this small population is not 85 mcg as the ATA said (Jonklaas et al 2014, quoted above), but 99.4 mcg/day.

However, before we jump to the conclusion that we should dose LT4 100 mcg per day to imitate the average daily amount of thyroid secretion, here’s an important fact to remember:

Thyroidal secretion of T4 or T3 is not physiologically or pharmacologically equivalent to oral dosing of thyroid hormone medication.

Let’s consider the adjustments that make today’s standard levothyroxine monotherapy incapable of approximating natural thyroidal secretion.

First of all, the dosing rate per day must be higher than the healthy human secretion rate per day partly because LT4 is poorly absorbed through the small intestine in the GI tract (Wiersinga et al, 2012).

Secondly, because thyroid patients with damaged or missing thyroid glands talking levothyroxine alone have no replacement for their T3 secretion, they need to achieve FT4 levels that are significantly higher than the population average (Jeon et al, 2019). This high-normal FT4 is necessary to maintain enough converted T3 in circulation to produce an euthyroid state when judged by TSH alone.

Even a mildly elevated FT4, once honestly called “chemical hyperthyroidism,” has long been considered acceptable in levothyroxine thyroid therapy (Rendell & Salmon, 1985). It’s essential to provide sufficient thyroid hormone even when FT4 in the top 1/5th of statistical reference range is a risky state associated with “sudden cardiac death” in males (van Noord et al, 2008).

As you can see, our traditions of levothyroxine therapy already prove that endocrinologists treating hypothyroidism cannot make dosing (and its biochemical results) perfectly imitate the average secretion rates and ratios found in untreated human beings.

Endocrinologists have accepted both the abnormality and the health risks within their preferred mode of LT4 monotherapy.

A ratio of 0% T3 from thyroidal secretion to 100% T3 from peripheral metabolism is physiologically incorrect, but it has been deemed acceptable in LT4 monotherapy.

Therefore, limiting either levothyroxine therapy or combination T3-T4 thyroid therapies strictly to the narrow statistical averages of thyroidal secretion found in Pilo’s healthy patients is unacceptably restrictive.

Yet this is exactly what our contemporary guidelines for T3-T4 combination therapy attempt to do (Wiersinga et al, 2012). It is a double standard to permit the unnatural, risky aspects of levothyroxine monotherapy while strictly forbidding all LT3 doses higher than the “physiological” average represented by patient #7 alone.

Bar graph of T3 secretion

Now instead of focusing on T3:T4 ratios and T4 secretion, let’s look at T3 secretion data using a bar graph.

The myth is that 20% of our daily T3 supply is secreted from the thyroid gland.

There is no central tendency in the data.

Which patient comes closest to the 20% average? It’s patient 8 this time.

Therefore, saying “the thyroid secretes 20% of one’s daily T3 supply” is extremely misleading.

Let’s do the endocrine math.

If your thyroid secretes a certain amount of T4 into your blood over a 24 hour period, you may convert anywhere from 16.9% to 42.9% of this T4 into T3 hormone (conversion “rate,” shown later, in graphs below).

This conversion “rate” of micrograms per day per meter of body surface area, when multiplied by each research subject’s body surface area, yields the net “amount” of thyroidal T3 in micrograms per day for each person.

You can then express the “thyroidal” micrograms of T3 as a percentage of their total micrograms of T3 produced per day. That’s what you see in the blue bar graph above.

The thyroid glands in this study contributed between 6.5% to 42.0% of the total daily T3 supply.

That is, you might be lucky to get that much T3 from your thyroid IF your TSH is between 1-2 and you have a healthy thyroid gland, as these 14 subjects did.

Even in a person whose T4 secretion is well regulated by a statistically-average TSH like these people’s was, it’s a roll of the dice how much T3 they’ll convert from their T4 in peripheral tissues. This wide-ranging, individualized conversion rate determines how much T3 their gland secretes daily to compensate.

Continue to Page 2:

• The shifting percent of T3 from peripheral conversion
• The total amount of T3 from peripheral conversion
• How does TSH affect secretion and conversion rate?
• How do sex and age influence these rates?
• What about health factors?
• Solutions?
• References